Cytoreductive therapy and allogeneic bone marrow or blood stem cell transplantation (HCT) is a treatment strategy that utilizes the administration of anti-cancer drugs and/or radiation therapy for the purpose of killing cancer cells and transplantation of hematopoietic cells to “rescue” or restore bone marrow blood and immune cell production. There can be significant side-effects, but type and severity of the side effects are influenced by the degree of HLA matching between donor and recipient; the condition and age of the patient; the specific treatment regimen; and the degree of suppression of the immune system.
Graft-versus-host disease is a common complication of allogeneic stem cell transplant. In this reaction, lymphocytes from the donor attack cells in the body of the recipient, particularly in the skin, gastrointestinal tract and liver. Common symptoms of acute graft-versus-host disease are skin rashes, jaundice, liver disease and diarrhea. Graft-versus-host disease also increases a patient's susceptibility to infection. Graft-versus-host disease can develop within days or as long as 3 years after transplantation. Graft-versus-host disease can also have an anti-cancer effect because donor lymphocytes can kill cancer cells as well as normal cells. When donor lymphocytes kill cancer cells, it can be referred to as graft-versus-tumor effect.
For patients who do not achieve or sustain a complete response to primary therapy, stem cell rescue by allogeneic HCT is often the treatment of choice. Allogeneic HCT can be considered a treatment option for select patients, especially those who have bone marrow involvement or who have relapse of diagnosis after autologous HCT. Allogeneic HCT can induce prolonged remissions and even cure some patients with chemotherapy refractory disease. An important mechanism of cancer eradication comes from the recognition of residual host tumor cells by donor-derived immune cells contained in the donor graft; termed the graft versus tumor (GVT) effect. This concept was initially developed from studies that used T-cell-depleted donor grafts in which graft-versus-host disease (GVHD) was eliminated. Without donor T-cells, patients suffered a high incidence of disease recurrence.
The demonstration that donor immune-mediated mechanisms are critical in controlling residual disease challenged the concept that relatively toxic full-dose chemoradiation is required for cure following allogeneic HCT. Transplant regimens that use significantly lower doses of chemoradiation, termed reduced intensity conditioning (RIC), that at the same time remain sufficiently immune-ablative to allow full donor hematopoietic cell engraftment have shifted the burden of tumor eradication to GVT effects. In an effort to reduce GVHD without compromising GVT reactions, a model has been developed for clinical practice where patients who receive low-dose total lymphoid irradiation (TLI) combined with depletive T-cell antibodies (anti-thymocyte serum) are infused with donor grafts. The majority of patients developed sustained donor-derived hematopoiesis and had a very low incidence of acute GVHD and non-relapse mortality.
Irrespective of whether a full dose or RIC transplant approach is pursued, relapse and disease progression remain the single largest cause of treatment failure after allogeneic HCT. Disease relapse after allogeneic HCT portends a poor outcome as typically allogeneic HCT was performed as a “last effort” for cure. Patients who experience relapse of lymphoma after allogeneic HCT remain in a unique circumstance in that they have progressive host-derived lymphoma with mixed (5-95%) or complete (>95%) donor hematopoietic cell chimerism. In some settings the 3-year cumulative risk of relapse after transplantation is 37% for patients who achieve complete donor hematopoietic cell chimerism and 78% among patients with mixed donor chimerism.
Interventions to treat relapsed disease included chemotherapy and/or radiation therapy (RT), withdrawal of immunosuppression or donor lymphocyte infusion (DLI). Despite these interventions, overall survival from time of relapse at 5 years is poor. Salvage treatment with radiation to bulky or symptomatic sites with or without chemotherapy induced responses in the majority of patients (>50%), yet the responses were generally of short duration (<6 months). Alternatively, in the absence of GVHD, DLI can be given yet this strategy is often complicated by the subsequent development of severe GVHD.